Immune responses are largely mediated by a diverse collection of peripheral blood cells termed leukocytes. The leukocytes include lymphocytes, granulocytes and monocytes. Granulocytes are further subdivided into neutrophils, eosinophils and basophils. Lymphocytes are further subdivided into T and B lymphocytes. T-lymphocytes originate from lymphocytic-committed stem cells of the embryo. Differentiation occurs in the thymus and proceeds through prothymocyte, cortical thymocyte and medullary thymocyte intermediate stages, to produce various types of mature T-cells. These subtypes include CD8.sup.+ T-cells (also known as cytotoxic/suppressor T-cells), which have the capacity to lyse target cells, and CD4.sup.+ T-cells (also known as T helper and T inducer cells), which have the capacity to stimulate other immune system cell types.
Immune system responses are elicited in several differing situations. The most frequent response is as a desirable protection against infectious microorganisms. However, undesired immune response can occur following transplantation of foreign tissue, or in an autoimmune disease, in which one of a body's own antigens is the target for the immune response. Immune responses can also be initiated in vitro by mitogens or antibodies against certain receptors. In each of these situations, an immune response is transduced from a stimulating event via a complex interaction of leukocytic cell types. However, the participating cell types and nature of the interaction between cell types may vary for different stimulating events.
Much progress has recently been made in understanding the complex cellular interactions through which immune responses are mediated. Regulation occurs as the result of various cellular signals transduced between cells via soluble, as well as surface-bound, molecular mediators. Signals may be transduced either between a soluble mediator and a cell-surface antigen or between two cell surface antigens. Soluble mediators include interleukins, colony stimulating factors and the interferons, which interact with their respective receptors, for example, the IL-2 receptor. Paired cell surface antigens include LFA-1, and the ICAM's (Staunton et al., Cell 52:925 (1988); Staunton et al., Nature 339:61 (1989); Vazeux et al., Nature 360:485 (1992); CD2 and LFA-3 (Selvaraj et al., Nature 326:400 (1987), CD8 and HLA Class I (Norment et al., Nature 336:79 (1988), CD4 and HLA Class II (Doyle et al., Nature 330:256 (1987), CD28 and B7 (Linsley et al., Proc. Natl. Acad. Sci. USA 87:5031 (1990), as well as whole families of selectins, addressins and integrins (reviewed by Mackay et al., Immunology Today 14:99 (1993); Springer, Nature 346:425-434 (1990)) (each of which is incorporated by reference for all purposes).
Many of the cell-surface antigens and receptors identified to-date have been classified as members of the immunoglobulin superfamily of proteins (IgSF). IgSF proteins are characterized by one or more disulfide-linked loops formed between a highly conserved and properly spaced pair of cysteine residues, which organizes two .beta.-sheets composed of seven or nine antiparallel .beta.-strands. These loops, which are referred to as immunoglobulin-like domains, are subclassified as variable or constant immunoglobulin-type domains. The variable, or V-type domains, generally possess disulfide loops with cysteines spaced by 65-75 amino acids and thus accommodate nine antiparallel .beta.-strands whereas the constant, or C-type, domains typically consist of intercysteine distances of 35-55 residues, and thus accommodate only seven antiparallel .beta.-strands. Although some IgSF members contain multiple domains of a single type (e.g., NCAM with five C2-type domains), most members consist of either a single Ig domain or a mixture of domains of both the V- and C-types. In most members having a single Ig domain, the domain is variable (e.g., CTLA-4/CD28, Thy-1, P.sub.0 (Williams et al., Ann. Rev. Immunol. 6:381 (1988); and newer members such as HB15 (Zhou et al., J. Immunol. 149:735 (1992), PD-1 (Ishida et al., EMBO J. 11:3887 (1992) and CMRF 35 (Jackson et al., European J. Immunol. 22:1157 (1992). In most members having multiple domains, the N-terminal domain (i.e., most externally orientated) is also usually of the variable type (e.g., all immunoglobulin and TCR chains, CD4, OX2, poly Ig receptor, carcinoembryonic antigen (reviewed in Williams et al., Ann. Rev. Immunol. 6:381 (1988) and newer members such as LAG-3 (Triebel et al., J. Exp. Med. 171:1393 (1990), Tactile (Wang et al., J. Immunol. 148:2600 (1992), CD33 (Simmons et al., J. Immunol. 141:2797 (1988) and BEN (Pourquie et al., Proc. Natl. Acad. Sci. USA 89:5261 (1992). The frequency with which V-type domains occur at the most externally oriented position suggests a particular importance of these domains in intercellular interactions.
The identification of signal-transducing cell-surface receptors has suggested new agents for suppressing undesirable immune responses such as transplant rejection, autoimmune disease and inflammation. Agents, particularly antibodies, that block receptors of immune cells from binding to soluble molecules or cell-bound receptors can impair immune responses. Ideally, an agent should block only undesired immune responses (e.g., transplant rejection) while leaving a residual capacity to effect desirable responses (e.g., responsive to pathogenic microorganisms). The immunosuppressive action of some agents, for example, antibodies against the CD3 receptor and the IL-2 receptor have already been tested in clinical trials. Although some trials have shown encouraging results, significant problems remain. First, a patient may develop an immune response toward the blocking agent preventing continued immunosuppressive effects unless different agents are available. Second, cells expressing the target antigen may be able to adapt to the presence of the blocking agent by ceasing to express the antigen, while retaining immune functions. In this situation, continued treatment with a single immunosuppressive agent is ineffective. Third, many agents, e.g., anti-CD3 antibodies, even though targeted against a specific receptor, effectively block all T-cell mediated immune responses, and thereby render a patient severely vulnerable to infection.
Based on the foregoing it is apparent that a need exists for additional and improved agents capable of suppressing immune responses, particularly agents capable of selective suppression. The present invention fulfills these and other needs, in part, by providing a novel cellular antigen as a novel target for immunosuppressive agents.